HCA2 activation in Pemphigoid Diseases - therapeutic effect and mode of action

在P8中，我们研究了使用富马酸二甲酯（DMF）治疗类天疱疮疾病（PD）的药理学基础。DMF在肠道中已经转化为富马酸单甲酯（MMF），这是G蛋白偶联受体HCA 2（GPR 109 A）的激动剂。事实上，我们发现证据表明，HCA 2介导了最近描述的口服DMF在大疱性类天疱疮（BP）样获得性大疱性表皮松解症（EBA）小鼠模型中的保护作用。因此，DMF改善了雌性Hcar 2 +/+小鼠的类天疱疮病样皮肤病变，但在Hcar 2-/-动物中未改善。出乎意料的是，溶剂处理的雌性Hcar 2-/-动物部分免受EBA的影响，表明HCA 2的Janus面功能：如果被内源性激动剂激活则是有害的，而对外源性应用的药物响应则是有益的。在第二次FP中，我们将研究这种矛盾功能的原因，以牢固地确立HCA 2作为治疗PD的药物靶点。首先，我们将通过改变饮食来仔细研究内源性HCA 2激活剂的作用，包括丁酸盐、β-羟基丁酸盐和烟酸。由于饮食相关代谢物对PD病理学的潜在影响可能对患者护理产生重要影响，因此我们将通过在小鼠和人类患者中进行代谢组学研究来寻找HCA 2激活的间接证据。其次，我们将定义介导内源性和药理学HCA 2激活剂作用的细胞类型。一个国家的最先进的调查这个问题是可能的，使用一种新的小鼠品系，我们已经产生，其中loxP位点已插入到Hcar 2基因座。如果靶细胞中没有完全重叠，我们的目标是将药理学HCA 2激活限制在身体区室，其中有益的作用占主导地位。第三，我们将解决内源性和药理学HCA 2激活剂，可以解释他们的不同行动的动力学概况。为了接近这一点，我们将确定BP患者口服给药后药物血浆浓度的动力学曲线，这些患者将成为由CRU联盟发起并由欧盟委员会资助的BP DMF临床试验的一部分，并将通过皮下植入的可调节泵输注化合物在小鼠中进行建模。

In P8, we have investigated the pharmacological basis of using dimethyl fumarate (DMF) in the treatment of pemphigoid diseases (PDs). Already in the gut, DMF is converted into monomethyl fumarate (MMF), an agonist of the G protein coupled receptor HCA2 (GPR109A). Indeed, we found evidence that HCA2 mediates the recently described protective effect of oral DMF in a mouse model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA). Thus, DMF ameliorated pemphigoid disease-like skin lesions in female Hcar2+/+ mice, but not in Hcar2-/- animals. Unexpectedly, vehicle-treated female Hcar2-/- animals were partially protected from EBA suggesting a Janus-faced function of HCA2: detrimental if activated by endogenous agonists and beneficial in response to exogenously applied drugs. In the 2nd FP, we will investigate the reason of this ambivalent function to firmly establish HCA2 as a drug target for the treatment of PDs. First, we will scrutinize the role of endogenous HCA2 activators, including butyrate, β-hydroxybutyrate, and nicotinic acid, by modifying the diet. As a potential effect of diet-related metabolites on PD pathology could have important ramifications for patient care, we will search for indirect evidence of HCA2 activation by performing metabolomic studies in mice and human patients. Second, we will define the cell type(s) that mediate effects of endogenous and pharmacological HCA2 activators. A state-of-the-art investigation of this question is possible using a novel mouse line, we have generated, in which loxP sites have been inserted into the Hcar2 locus. If there is no complete overlap in the target cells, we will aim to limit pharmacological HCA2 activation to the body compartment, in which beneficial effects prevail. Third, we will address the kinetic profiles of endogenous and pharmacological HCA2 activators that may explain their distinct actions. To approach this point, we will determine the kinetic profile of the drug’s plasma concentrations after oral administration in BP patients, who will be part of the clinical trial on DMF in BP, initiated by the CRU consortium and funded by the EU commission, and will model it in mice by infusing the compound through a subcutaneously implanted adjustable pump.